title: The leukemia-associated Mll-Ell oncoprotein induces fibroblast growth factor 2 (Fgf2)-dependent cytokine hypersensitivity in myeloid progenitor cells.
abstract: The subset of acute myeloid leukemias (AML) with chromosomal translocations involving the MLL gene have a poor prognosis (referred to as 11q23-AML). The MLL fusion proteins that are expressed in 11q23-AML facilitate transcription of a set of HOX genes, including HOXA9 and HOXA10. Because Hox proteins are transcription factors, this suggests the possibility that Hox target genes mediate the adverse effects of MLL fusion proteins in leukemia. Identifying such Hox target genes might provide insights to the pathogenesis and treatment of 11q23-AML. In the current study we found that Mll-Ell (an MLL fusion protein) induced transcriptional activation of the FGF2 gene in a HoxA9- and HoxA10-dependent manner. FGF2 encodes fibroblast growth factor 2 (also referred to as basic fibroblast growth factor). Fgf2 influences proliferation and survival of hematopoietic stem cells and myeloid progenitor cells, and increased Fgf2-expression has been described in AMLs. We determined that expression of Mll-Ell in myeloid progenitor cells resulted in autocrine production of Fgf2 and Fgf2-dependent cytokine hypersensitivity. Therefore, our results implicated increased Fgf2 expression in progenitor proliferation and expansion in 11q23-AML. Because small molecule inhibitors of Fgf-receptors are in human clinical trials, this suggested a potential therapeutic approach to this treatment refractory leukemia.
authors.affiliation: From The Feinberg School of Medicine and Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, Illinois 60611.
authors.forename: Chirag A
authors.initials: CA
authors.lastname: Shah
authors.affiliation: From The Feinberg School of Medicine and Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, Illinois 60611; the Jesse Brown Veterans Administration Medical Center, Chicago, Illinois 60612.
authors.forename: Ling
authors.initials: L
authors.lastname: Bei
authors.affiliation: From The Feinberg School of Medicine and Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, Illinois 60611.
authors.forename: Hao
authors.initials: H
authors.lastname: Wang
authors.affiliation: From The Feinberg School of Medicine and Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, Illinois 60611; the Jesse Brown Veterans Administration Medical Center, Chicago, Illinois 60612.
authors.forename: Leonidas C
authors.initials: LC
authors.lastname: Platanias
authors.affiliation: From The Feinberg School of Medicine and Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, Illinois 60611; the Jesse Brown Veterans Administration Medical Center, Chicago, Illinois 60612. Electronic address: e-eklund@northwestern.edu.
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Eklund
mesh_terms: D000818:Animals; D019898:Autocrine Communication; D016207:Cytokines / Q000096:biosynthesis* / Q000235:genetics; D016222:Fibroblast Growth Factor 2 / Q000096:biosynthesis* / Q000235:genetics; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D023461:Myeloid Progenitor Cells / Q000378:metabolism / Q000473:pathology; D051788:Myeloid-Lymphoid Leukemia Protein / Q000096:biosynthesis* / Q000235:genetics; D015514:Oncogene Proteins, Fusion / Q000096:biosynthesis* / Q000235:genetics; D015533:Transcriptional Activation; D020298:U937 Cells
chemical_list: D016207:Cytokines; C472772:MLL-ELL fusion protein, human; D015514:Oncogene Proteins, Fusion; D016222:Fibroblast Growth Factor 2; D051788:Myeloid-Lymphoid Leukemia Protein
keywords: Cell Proliferation; Fibroblast Growth Factor (FGF); Gene Transcription; Growth Factors; Leukemia; hox; mll